The development of a safe and effective vaccine against HIV-1 is critical for curtailing the spread of a primarily sexually transmitted disease that is now affecting more than 30 million persons worldwide. While a recent poxvirus-protein immunogen efficacy trial conferred modest protection from acquisition, the correlates of protection are unknown. In the SIV infection model in Rhesus macaques, up to 70% of animals, vaccinated with GM-CSF enhanced DNA priming, MVA boosted, then subjected to a heterologous (E660), multiple low dose rectal challenge, were protected from acquisition and a clear correlate of protection was E660 Env binding antibody avidity. The Emory Consortium for B-Cell Biology of Mucosal Immune Protection from SIV Challenge, using highly collaborative approaches, will define through advanced immunological and systems biology approaches the underlying mechanisms for enhanced antibody avidity and protection. The Consortium will incorporate four research projects and four science support cores, in addition to an Administrative core to achieve this goal. Project 1 will identify the mechanisms by which GM-CSF mediates enhanced protection from low dose SIV vaginal challenge, and will determine whether addition of an optimized protein boost further enhances protection. Project 2 will investigate the potential and underlying mechanism for TLR-4 and TLR-7 ligands, delivered in a novel synthetic nanoparticle formulation and recently shown to dramatically improve antibody responses to influenza HA, to enhance the quality of protective mucosal B-cell and T-cell responses to SIV VLPs. Project 3 will determine the effects of GM-CSF and nanoparticle delivered TLR ligand adjuvants on follicular T-cells and their function in molding the quality of the humoral immune response, while Project 4 will similarly investigate the potential for these adjuvanting approaches to activate a subset of IL-21 producing N{BH} neutrophils equipped with B cell helper function. The projects will be supported by an NHP Core, which will provide and maintain genetically characterized female macaques for the studies. Additional Cores will allow characterization of the antiviral antibody response at the level of single cells and mucosal secretions, and a B-cell biomarker core will develop unique reagents for defining the B-cell response in this rhesus model. The Administrative Core will ensure effective communication and collaboration between projects and Cores through database and repository management and will be responsible for maintaining timelines, fiscal responsibility, and dissemination of research results.